The present invention relates to the treatment of hypogonadism in men, whether due to an absolute or relative deficiency of testosterone. More specifically, the invention relates to compositions comprising a pharmaceutically effective dose of ethisterone or an ethisterone derivative such as [1,2], oxazolo[4,5-b]17alpha-pregna-2,4-dien-20-yn-17beta-ol; also known as danazol, Danol, Azol (in Australia) and Danocrine (in the USA). 
Androgen Deficiency in the Ageing Male, also referred to as xe2x80x98The Male Climatericxe2x80x99, xe2x80x98The male menopausexe2x80x99 and the xe2x80x98Andropausexe2x80x99 causes a highly characteristic pattern of symptoms which was first recognised nearly sixty years ago (Werner, A. JAMA 112, 15, 1441-3, 1939). As described at that time, the syndrome includes loss of energy, drive and libido, depression, irritability, joint pains and stiffness, and even such typical symptoms of the female menopause as night sweats and hot flushes.
It has been found (Carruthers, M. xe2x80x98The Male Menopause, Harpercollinsxe2x80x99, London, 1996) that the symptoms associated with this condition arise due to an absolute or relative insufficiency of testosterone, particularly the latter, caused by a reduction in the Free Active Testosterone (FAT); that is a lack of testosterone present in an unbound state in blood plasma. Testosterone in vivo can be bound to sex hormone binding globulin (SHBG) and to a lesser extent, albumin. When bound the testosterone is not freely available to the body or bio-available. One of the best measures of this is the xe2x80x98Free Androgen Indexxe2x80x99 (FAI). This is calculated by dividing the Total Testosterone (TT) by the xe2x80x98sex Hormone Binding Globulinxe2x80x99 (SHBG) and multiplying by a hundred to express it as a percentage. In the healthy, asymptomatic male this is normally in the range 70-100%. Symptoms of the andropause regularly appear when this drops below 50%, except in a few cases where the TT is low and the body appears to compensate by reducing SHBG levels to maintain the FAI.
It has been found that hypogonadism and also the male menopause can be prevented or treated by freeing bound testosterone so that it becomes bioavailable again. Testosterone may be freed, for example, by:
1. decreasing the number of potential binding sites available for testosterone in vivo, for example by reducing the level of SHBG using compounds which antagonise the action of androgens in stimulating SHBG synthesis, and/or
2. introducing an agent which competes for the binding sites, thereby displacing bound testosterone which is returned to systemic circulation.
Pharmaceutical, pharmacological and biological compounds that may act effectively include ethisterone and ethisterone derivatives and/or precursors.
One such compound, danazol, is a well established therapeutic agent which has been extensively used in the female for managing a wide range of conditions such as endometriosis, menorrhagia and benign breast conditions such as mastalgia and cystic disorders. Its use in the male is not widely known and has been limited to treatment of enlargement of the male breast (gynaecomastia) and limited research into its use as a male contraceptive. The previous uses of danazol in women and men have all been at relatively high concentrations, for example doses of 200 to 600 mg, and at these concentrations it has been shown that total plasma testosterone is reduced.
It has now been found that using danazol in the male at dose level reduced from that at which it would be conventionally used, for example at a daily dose of not more than 100 mg, re-introduction of testosterone to the systemic circulation in the form of Free Active Testosterone is remarkably effective; that is the FAT is increased leading to a highly effective treatment of the symptoms associated with hypogonadism and with the male menopause.
Danazol is effective, non-hepatotoxic, and does not have intrinsic androgenic, oestrogenic or progestogenic actions. It is an ideal agent for displacing and hence activating testosterone as it has a high affinity for androgen receptors, low affinity for progesterone receptors, and does not interact with oestrogen receptors to any significant extent
The importance of only giving low doses of danazol, for example not more than 50-100 mg daily, to men being treated for hypogonadism is because at this low dose, as shown by the clinical studies described later in this application, there is direct suppression of SHBG synthesis by the liver, with a corresponding increase in FAI, apparently without reduction of endogenous total testosterone production.
According to the present invention, danazol is used in the manufacture of a medicament for the treatment of hypogonadism in the male.
The medicament may be for treatment of hypogonadism resulting from any biological or physical cause. In particular, the medicament may be for treatment of any condition where systemic free active testosterone is reduced due to raised levels of SHBG, for example, conditions caused by concurrent/prior treatment with oestrogens, anti-convulsants and/or exposure to xeno-oestrogens.
The medicament may be for treatment of male humans. The medicament may also be a veterinary pharmaceutical preparation for treatment of male animals (such as bulls or rams) where symptoms of hypogonadism are a problem, for example in breeding stock.
Preferably, the danazol is used in the manufacture of a medicament for the treatment of male menopause.
Preferably not more than 100 mg of danazol, [1,2]oxazolo[4, 5-b]-17alpha-pregna-2,4-dien-20-yn-17beta-ol, is used per daily dose in the manufacture of the medicament, preferably the daily dose of [1,2]oxazolo[4,5-b]-17alpha-pregna-2,4-dien-20-yn-17beta-ol is between 25-100 mg. The dose is varied according to body weight, TT and SHBG concentrations.
Danazol may be administered on its own or as an adjunct to other methods of relieving sexual dysfunction problems in men such as libido disorders and impotence, such as applications of alprostadil (Caverject and Medicated Urethral Systems for Erectionxe2x80x94MUSE), and drugs which enhance relaxation of the corpora cavernosae in the penis, for example those which increase nitric oxide production such as the oral preparation sildenafil (Viagra).
According to the present invention in a further aspect danazol, together with testosterone is used in the manufacture of a medicament for the treatment of the male menopause.
Preferably the testosterone is synthetic. It will be appreciated that the action of natural and endogenous testosterone is also enhanced when using the medicament.
Preferably not more than 100 mg of [1,2],oxazolo[4,5-b]-17alpha-pregna-2,4-dien-20-yn-17beta-ol is used with testosterone per daily dose in the manufacture of the medicament, preferably the daily dose of [1,2],oxazolo[4,5-b]-17alpha-pregna-2,4-dien-20-yn-17beta-ol is between 25-100 mg. Preferably, the daily dose of testosterone used in the manufacture of the medicament is in the range of 80-240 mg. The doses of [1,2],oxazolo[4,5-b]-17alpha-pregna-2,4-dien-20-yn-17beta-ol and testosterone are varied according to body weight, TT and SHBG concentrations
According to a still further aspect of the invention there is provided a pharmaceutically acceptable medicament in a dosage form of 25 mg or 50 mg or 75 mg or 100 mg per day of danazol and excipient.
Preferably the pharmaceutically acceptable medicament also includes testosterone.
According to a still further aspect of the invention there is provided a pharmaceutically acceptable medicament which includes danazol and testosterone.